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J Nakura

Publications and source records attributed to J Nakura.

At least 37 records · Page 2Linked to original sources
PubMed1996

Homozygous and compound heterozygous mutations at the Werner syndrome locus.

The Werner syndrome (WS) is a rare autosomal recessive progeroid disorder. The Werner syndrome gene (WRN) has recently been identified as a member of the helicase family. Four distinct mutations were previously reported in three Japanese and one Syrian WS pedigrees. The latter mutation was originally described as a 4 bp deletion spanning a spliced junction. It is now shown that this mutation results in a 4 bp deletion at the beginning of an exon. Nine new WRN mutations in 10 additional WS patients, both Japanese and Caucasian, are described. These include three compound heterozygotes (one Japanese and two Caucasian). The new mutations are located all across the coding region.

Asian People↗
PubMed1996

Toward localization of the Werner syndrome gene by linkage disequilibrium and ancestral haplotyping: lessons learned from analysis of 35 chromosome 8p11.1-21.1 markers.

Werner syndrome (WS) is an autosomal recessive disorder characterized by premature onset of a number of age-related diseases. The gene for WS, WRN, has been mapped to the 8p 11.1-21.1 region with further localization through linkage disequilibrium mapping. Here we present the results of linkage disequilibrium and ancestral haplotype analyses of 35 markers to further refine the location of WRN. We identified an interval in this region in which 14 of 18 markers tested show significant evidence of linkage disequilibrium in at least one of the two populations tested. Analysis of extended and partial haplotypes covering 21 of the markers studied supports the existence of both obligate and probable ancestral recombinant events which localize WRN almost certainly to the interval between D8S2196 and D8S2186, and most likely to the narrower interval between D8S2168 and D8S2186. These haplotype analyses also suggest that there are multiple WRN mutations in each of the two populations under study. We also present a comparison of approaches to performing disequilibrium tests with multiallelic markers, and show that some commonly used approximations for such tests perform poorly in comparison to exact probability tests. Finally, we discuss some of the difficulties introduced by the high mutation rate at microsatellite markers which influence our ability to use ancestral haplotype analysis to localize disease genes.

Age of Onset↗
PubMed1995

Genetic association between chromosome 8 microsatellite (MS8-134) and Werner syndrome (WRN): chromosome microdissection and homozygosity mapping.

Werner syndrome (WRN) is an autosomal recessive disorder characterized by premature aging that has been mapped to the short arm of chromosome 8, 8p11.2-p12. To refine the genetic map around the WRN region, we have isolated eight microsatellites for this region from a microdissection library. We typed members of Japanese families with WRN on the basis of homozygosity mapping analysis. There was no obligate recombination between the WRN locus and microsatellite clone, MS8-134 (D8S1055). The maximum lod score was 20.28 at theta = 0.00. Alleles for MS8-134 showed association with WRN in a case-control study (OR = 3.55, 95% CI 1.56-8.07, P < 0.01). Such microsatellites from a microdissection library of the definite chromosome region may be useful for positional cloning of the WRN gene.

Base Sequence↗
PubMed1995

[Genetic analysis of Werner syndrome in a family].

Werner syndrome (WRN) is a rare autosomal recessive disorder, one of the progeroid syndromes, and is characterized by features of premature aging. The incidence of WRN in the Japanese population, 1 in 200,000, is higher than than that in the Caucasian population. The genetic defect of WRN is unknown. But genetic linkage to several markers on the short arm of chromosome 8 has been reported recently. Here, we studied one family with WRN in which an affected individual had a papillary thyroid carcinoma and myelodysplastic syndrome. Using 4 microsatellites closely located to the WRN locus: D8S360, D8S1055, D8S339 and ANK1, we analyzed the genotypes of this patient, her three siblings and her parents, who were first cousins. The mutative haplotype, identified through the generations in pedigree, helps detect a carrier or a presymptomatic patient. The eldest sister inherited two normal haplotypes, but the second sister inherited one mutative haplotype. There was no difference in clinical signs and symptoms between these sisters. when the WRN gene is isolated, it will help us understand the mechanism of aging.

Adult↗
PubMed1994

Homozygosity mapping of the Werner syndrome locus (WRN).

Werner syndrome (WS) is an autosomal recessive disorder characterized by the early onset of several age-related diseases. The locus for this disease was recently mapped to 8p12. We studied 27 WS kindreds of mixed ethnic origins, 26 of which were consanguineous. In 24 of these families, the affected subject was given the diagnosis of "definite" WS and affected subjects in the remaining 3 pedigrees were given the diagnosis of "probable" WS. Affected subjects from each kindred were genotyped for 13 short tandem repeat polymorphic sites. Two-point linkage analysis yielded significant evidence for linkage to D8S137, D8S339, D8S87, PLAT, D8S165, and D8S166. The locus yielding a maximum lod score at the smallest recombination fraction was D8S339, suggesting that this marker is the closest to the WS gene (WRN locus) of those tested. D8S339 gave significant lod scores (Zmax > or = 3.0) for both Japanese and non-Japanese (mostly Caucasian) families, demonstrating that a single locus is responsible for WS in both groups. Multipoint analysis of these markers yielded a maximum lod score of 17.05 at a distance of approximately 0.6 cM from D8S339. The combined evidence from 2-point analysis, multipoint analysis, and analysis of regions of homozygosity in subjects from inbred pedigrees indicates that the WRN locus is between D8S131 and D8S87, in an 8.3-cM interval containing D8S339.

Alleles↗
PubMed1994

Evidence against DNA polymerase beta as a candidate gene for Werner syndrome.

Werner syndrome (WS) is a rare autosomal recessive disorder of humans characterized by the premature onset and accelerated rate of development of several major age-related disorders. An aberration in DNA replication or repair is suggested by the evidence of genome instability. Since the structural gene for DNA polymerase beta maps within the region of the WS mutation on the short arm of chromosome 8 and is involved in both DNA repair and DNA replication, we evaluated its candidacy as the WS gene. Several independent lines of evidence did not support that hypothesis: (1) activity gels showed normal enzyme activity and electrophoretic mobility; (2) nucleotide sequence analysis of the entire coding region failed to reveal mutations (although indicated mistakes in the published sequence); (3) single-strand conformation polymorphism (SSCP) and heteroduplex analyses failed to reveal evidence of mutations in the promoter region; (4) a newly discerned polymorphism failed to reveal evidence of homozygosity by descent in a consanguineous patient; and 5) fluorescence in situ hybridization (FISH) analysis placed the DNA polymerase beta gene centromeric to D8S135 at 8p11.2 and thus beyond the region of peak LOD scores for WS.

Cell Line↗
PubMed1994

Carrier detection of Werner's syndrome using a microsatellite that exhibits linkage disequilibrium with the Werner's syndrome locus.

Werner's syndrome (WS) is a rare autosomal recessive disorder, one of the progeroid syndromes, characterized by features of premature aging. The genetic defect in WS is unknown but recently the genetic linkage of WS to several markers on the short arm of chromosome 8 has been reported. Genetic analysis of 25 families with WS demonstrated that D8S339 was the closest marker linked to the gene locus for Werner's syndrome (WRN), with a peak lod score of 18.29 at recombination frequency 0.001, and showed a linkage disequilibrium with the WRN locus. We studied two unrelated families with WS using ANK1, D8S339, and D8S360. The mutative haplotype identified through the generations in pedigrees provides a means of carrier detection and presymptomatic diagnosis.

Female↗